A LRRK2-Dependent EndophilinA Phosphoswitch Is Critical for Macroautophagy at Presynaptic Terminals.
Neuron. 2016-11-01; 92(4): 829-844
DOI: 10.1016/j.neuron.2016.09.037
Lire sur PubMed
1. Neuron. 2016 Nov 23;92(4):829-844. doi: 10.1016/j.neuron.2016.09.037. Epub 2016
Oct 6.
A LRRK2-Dependent EndophilinA Phosphoswitch Is Critical for Macroautophagy at
Presynaptic Terminals.
Soukup SF(1), Kuenen S(1), Vanhauwaert R(1), Manetsberger J(1), Hernández-Díaz
S(1), Swerts J(1), Schoovaerts N(1), Vilain S(1), Gounko NV(1), Vints K(1), Geens
A(1), De Strooper B(1), Verstreken P(2).
Author information:
(1)VIB Center for Brain & Disease Research, Leuven Institute for
Neurodegenerative Disease, 3000 Leuven, Belgium; KU Leuven, Department for Human
Genetics, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium.
(2)VIB Center for Brain & Disease Research, Leuven Institute for
Neurodegenerative Disease, 3000 Leuven, Belgium; KU Leuven, Department for Human
Genetics, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium.
Electronic address: .
Synapses are often far from the soma and independently cope with proteopathic
stress induced by intense neuronal activity. However, how presynaptic
compartments turn over proteins is poorly understood. We show that the
synapse-enriched protein EndophilinA, thus far studied for its role in
endocytosis, induces macroautophagy at presynaptic terminals. We find that
EndophilinA executes this unexpected function at least partly independent of its
role in synaptic vesicle endocytosis. EndophilinA-induced macroautophagy is
activated when the kinase LRRK2 phosphorylates the EndophilinA-BAR domain and is
blocked in animals where EndophilinA cannot be phosphorylated.
EndophilinA-phosphorylation promotes the formation of highly curved membranes,
and reconstitution experiments show these curved membranes serve as docking
stations for autophagic factors, including Atg3. Functionally, deregulation of
the EndophilinA phosphorylation state accelerates activity-induced
neurodegeneration. Given that EndophilinA is connected to at least three
Parkinson’s disease genes (LRRK2, Parkin and Synaptojanin), dysfunction of
EndophilinA-dependent synaptic macroautophagy may be common in this disorder.
Copyright © 2016 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.neuron.2016.09.037
PMID: 27720484 [Indexed for MEDLINE]